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Gene expression profile of human ovarian cancer cell lines in vitro

ABSTRACT: We have previously described how TNF-α, IL-6, CXCR4 and the CXCR4 ligand CXCL12 are expressed by human ovarian cancer cells in vitro. By comparing four ovarian cancer cell lines with varying levels of constitutive TNF-α production we found that CXCR4, CXCL12, TNF-α and IL-6 were linked in an autocrine network in malignant cells that had an effect on tumour growth and angiogenesis in one xenograft model of ovarian cancer. Using Affymetrix microarrays we compared in vitro gene expression in parental IGROV-1 and TOV21 cells (high CXCR4 expression) with TOV112D and SKOV-3 cells (low CXCR4 expression). Gene Set Enrichment Analysis (GSEA) of those genes which were differentially expressed between cell lines with high versus low CXCR4 expression revealed evidence for a cell autonomous signaling network involving CXCR4, TNF-a, IL6 and Notch pathways in ovarian cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18680 | GEO | 2009/12/31

SECONDARY ACCESSION(S): PRJNA121557

REPOSITORIES: GEO

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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Gene expression profile of human ovarian cancer cell lines in vitro

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